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PMID: 12242153 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

beta4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium.

Cancer cell ·Vol. 2 ·No. 3 ·2002-09-00 ·Pages 205-16

Weaver VM, Lelièvre S, Lakins JN, Chrenek MA, Jones JC, Giancotti F, Werb Z, Bissell MJ

Abstract

Tumor cells can evade chemotherapy by acquiring resistance to apoptosis. We investigated the molecular mechanism whereby malignant and nonmalignant mammary epithelial cells become insensitive to apoptosis. We show that regardless of growth status, formation of polarized, three-dimensional structures driven by basement membrane confers protection to apoptosis in both nonmalignant and malignant mammary epithelial cells. By contrast, irrespective of their malignant status, nonpolarized structures are sensitive to induction of apoptosis. Resistance to apoptosis requires ligation of beta4 integrins, which regulates tissue polarity, hemidesmosome formation, and NFkappaB activation. Expression of beta4 integrin that lacks the hemidesmosome targeting domain interferes with tissue polarity and NFkappaB activation and permits apoptosis. These results indicate that integrin-induced polarity may drive tumor cell resistance to apoptosis-inducing agents via effects on NFkappaB.

MeSH Terms
Apoptosis/physiology Basement Membrane/metabolism Breast Neoplasms/metabolism,pathology Cell Polarity Epithelial Cells/cytology,metabolism Extracellular Matrix/metabolism,ultrastructure Female Gene Expression Regulation, Neoplastic Humans Integrin beta4/metabolism,ultrastructure NF-kappa B/metabolism Tumor Cells, Cultured
Chemicals
Integrin beta4 NF-kappa B
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Weaver Valerie M
Department of Pathology and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA. wmweaver@mail.med.upenn.edu
Lelièvre Sophie
Lakins Johnathon N
Chrenek Micah A
Jones Jonathan C R
Giancotti Filippo
Werb Zena
Bissell Mina J
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1535-6108
DOI
10.1016/s1535-6108(02)00125-3
Email
wmweaver@mail.med.upenn.edu
Published
2002-09-00
Pages
205-16
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC2788997
Subset
IM
Grants
NCI NIH HHS · CA 64786 · United States
NCI NIH HHS · R01 CA078731 · United States
NCI NIH HHS · R37 CA064786 · United States
NCI NIH HHS · R01 CA064786-05 · United States
NCI NIH HHS · CA 57621 · United States
NCI NIH HHS · R01 CA057621 · United States
NCI NIH HHS · R01 CA057621-07 · United States
NCI NIH HHS · R01 CA078731-02 · United States
NCI NIH HHS · CA 78731 · United States
NCI NIH HHS · R01 CA064786 · United States
External Links
PubMed source DOI: 10.1016/s1535-6108(02)00125-3 PMC Full Text View journal details
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